Although the association between the APOE4 allele and Alzheimer's Disease (AD) has been recognized for over five years, the function(s) of apoE in the brain that are compromised by APOE4 are not understood. The clinical symptoms and cell biology of AD suggest many cellular mechanisms that could be affected by APOE genotype, including cytoskeletal function, protein disposition and clearance, vascular integrity, inflammation and oxidation, among others. We have undertaken an analysis of the apoE knockout mouse to gain insight into the function of apoE in the nervous system and to formulate hypothesis to explain the link between APOE4 and AD. We have discovered the following defects in apoE knockout mice: 1) extravasation of serum proteins from the vasculature into the apoE knockout brain , demonstrating a compromised blood brain barrier (BBB); 2) brain-region specificity in the breakdown of the BBB; and 3) accumulation of free immunoglobulin light chains in brain and peripheral tissues. These observations support roles for apoE in maintaining the integrity of the BBB and/or facilitating protein resorption within the brain. These results also give credence to long-standing hypotheses that AD is associated with microvascular defects, which may be involved in the disease mechanism. Our proposed experiments are designed to test whether apoE plays a role in maintaining the integrity of tight functions within the CNS vascular endothelium and/or in the cellular trafficking of proteins by endocytosis or transcytosis. In addition, we will determine whether the apoE isoforms differ in their ability to maintain BBB integrity by employing apoE transgenic mice. This analysis will provide insight into the functions of apoE in the brain and will lead directly to hypotheses regarding therapies for AD and other neural injuries.